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Y Nomoto

Publications and source records attributed to Y Nomoto.

At least 37 records · Page 2Linked to original sources
PubMed1998

[Radiotherapy in the treatment of brain metastasis from small cell lung carcinoma: study on appropriately controlled dose].

Fifty-two brain metastatic lesions occurring in 20 patients with small cell lung carcinoma (SCLC) were irradiated, and then the relationship between tumor size, dose and control was clinically and histopathologically studied. Lesions of 8 mm in diameter and those of 10 mm in diameter were determined to be controllable by irradiation at about 38 Gy and 42 Gy, respectively. According to size-dependent curative minimum doses, the lesions could be divided by the 10 Gy/ 5fr/wk method into controlled and non-controlled groups with the curve expressed as dose (Gy) = 15.27 log10 [tumor volume (mm3)] +0.6. Based on these results, tumors of 2 mm and 3 mm in diameter were estimated to be controllable at 14 and 20 Gy, respectively. Thus prophylactic cranial irradiation (PCI) in the treatment of SCLC was thought to be not always necessary if early treatment of small metastatic lesions, detected by Gd-DTPA-enhanced MRI could be achieved. The optimal interval between follow-up examinations was thought to be 1 month during the first two years after the diagnosis of SCLC, and then 3 months after that. In addition, the omission of PCI can save many patients who do not actually require PCI from suffering its adverse effects.

Aged↗
PubMed1997

Detection of group C adenovirus DNA in small-cell lung cancer with the nested polymerase chain reaction.

Group C adenovirus is latent in human tissues and can malignantly transform cells. The purpose of this study was to investigate the association between this virus and lung cancer. We investigated latent adenoviral infection using the nested polymerase chain reaction and in situ hybridization in transbronchial biopsy specimens from patients with small-cell lung cancer and non-small-cell lung cancer. The polymerase chain reaction was performed on DNA extracts with two sets of primers directed at a 261-base-pair target sequence of the E1A region of the adenoviral genome. In situ hybridization was performed on histological sections using DNA representing the entire adenovirus type 5 genome. E1A target DNA was present in 11 (31%) of 35 cases of small-cell lung cancer but in none of the 40 cases of non-small-cell lung cancer (P < 0.01). Of the 11 cases found positive by PCR, 8 were positive for adenovirus DNA by in situ hybridization. Adenovirus was prominent in tumor cells in 5 of the 8 cases, and in normal epithelial cells in the 3 remaining cases. Adenovirus DNA was not detected by in situ hybridization in specimens in which E1A DNA was not detected by the polymerase chain reaction. Small-cell lung cancer has mutations or deletions in the p53 and retinoblastoma genes more frequently than are found in non-small-cell lung cancer. Therefore, we speculate that adenovirus infection might participate in the pathogenesis of SCLC by producing mutation in these genes, rather than by inhibiting the function of these proteins.

Adenoviridae↗
PubMed1997

High dose rate endobronchial brachytherapy using a new applicator.

BACKGROUND AND PURPOSE: To obtain adequate spatial dose distribution for endobronchial brachytherapy, we applied reference dose points according to the bronchial diameter. For this purpose, we devised a new applicator of which the source transfer tube is contained in the center of the lumen for high dose rate (HDR) brachytherapy. MATERIALS AND METHODS: Thirty-nine patients with endobronchial cancer underwent endobronchial brachytherapy using an HDR afterloading machine with an Ir-192 source. In the nine patients treated with curative intent, treatment consisted of external beam radiotherapy with 40-60 Gy for 4-6 weeks and endobronchial brachytherapy with three fractions of 6 Gy. The 30 patients treated with palliative intent received one fraction of 10 Gy with or without external beam irradiation. The reference dose points were prescribed according to bronchial diameter, which was measured by the applicator's radiopaque wing expansion reflecting the bronchial caliber. RESULTS: The new applicator could be placed at the intended site in 37 lesions. Of 12 lesions which were treated with curative intent, eight (67%) disappeared after brachytherapy. The overall survival at 3 years of all patients and of the patients treated with curative intent was 22 and 64%, respectively. CONCLUSIONS: The source should be positioned in the center of the lumen; this technique is helpful in reducing side-effects caused by inhomogeneous dose distribution of endobronchial brachytherapy.

Adult↗
PubMed1997

Glomerular Fc alphaR expression and disease activity in IgA nephropathy.

In this study, we examined the receptors for the Fc portion of immunoglobulin A (IgA) (Fc alphaR) in the glomeruli as well as circulating polymorphonuclear leukocytes and monocytes at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR) assay and at the protein level by an immunohistochemistry/flow cytometry technique using a specific anti-Fc alphaR monoclonal antibody (My 43). Glomeruli were isolated from biopsy specimens of renal tissues from IgA nephropathy (IgAN; 20 cases) and non-IgA mesangial proliferative glomerulonephritis (PGN; 13 cases) patients, and from normal renal tissue specimens obtained from kidneys removed because of malignancies (five cases) applying the microdissection method. There was a relative increase in Fc alphaR in the circulating phagocytes from IgAN patients compared with those from PGN and healthy controls. Fc alphaR expression was present in approximately 40% of glomeruli samples from IgAN patients at the message levels. Fc alphaR-positive specimens were also strongly positive for expression of tumor necrosis factor-alpha, interleukin-1, and interleukin-6 mRNA. Specimens from PGN patients and healthy controls did not show any detectable Fc alphaR message. Serum IgA levels and severity of hematuria were significantly higher in patients with positive Fc alphaR expression. A message for Fc alphaR was detected in the tissues that were more damaged histologically. Our data suggest that there is some in vivo induction of glomerular Fc alphaR expression, possibly mediated by a synergistic stimulus from IgA and inflammatory cytokines, and the expressed receptor is likely to be involved in the disease process of IgAN.

Antigens, CD↗
PubMed1997

Phenotypic characterization of cytokine expression in patients with IgA nephropathy.

To identify the cytokines that play a relevant role in the pathogenesis of IgA nephropathy, we analyzed and compared the gene expression of proinflammatory cytokines, immuno-regulatory cytokines, and growth factors in peripheral blood mononuclear cells (PBMC). Expression of IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-gamma, TGF-beta, TNF-alpha, and PDGF was examined in 28 patients with IgA nephropathy (IgAN), 20 patients with non-IgA mesangial proliferative glomerulonephritis (mesPGN), and 19 healthy controls. Compared with healthy controls, a significant number of IgAN and mesPGN patients showed increased expression of IL-1 beta, IL-4, IL-10, IL-12, and IFN-gamma. The cytokine profile of renal tissue of 10 IgAN and 5 mesPGN biopsies was simultaneously analyzed and compared with that of PBMC. The proinflammatory IL-1 alpha and growth factor PDGF-B were expressed more in renal tissues than in PBMC. Furthermore, the renal profile of IL-alpha, IFN-gamma, and TNF-alpha expression was associated with the expression of IFN-gamma in PBMC. The serum level of IFN-gamma of IgAN correlated significantly (P = 0.0003) with that of IL-12, suggesting a potential role for cross-stimulation. More importantly, expression of IFN-gamma in PBMC and the elevated serum level correlated with the decline in glomerular filtration rate (P = 0.0012) and severity of renal histopathologic grade. To elucidate the role of leukocytes in renal cytokine expression, surface markers of T cells (CD3), monocytes (CD14), natural killer cells (CD16), and B cells (CD19) were also examined in renal tissues. The prominent renal expression of CD3, CD14, and CD16 implicates the leukocytes as the major source of proinflammatory cytokines in IgAN. Collectively, these findings indicate that IFN-gamma plays a prominent role in an interactive network of cytokines that contribute to the pathogenesis and progression of IgA nephropathy.

Adult↗
PubMed1997

Anti-tumour activities of a new benzo[c]phenanthridine agent, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phena nthridini um hydrogensulphate dihydrate (NK109), against several drug-resistant human tumour cell lines.

Drug resistance is one of the problems severely limiting chemotherapy in cancer patients. Thus, it is very important to develop new drugs that are effective against drug-resistant tumour cells. The novel anti-tumour agent NK109 has been developed from benzo[c]phenanthridine derivatives by Nippon Kayaku (Tokyo, Japan). We have confirmed that NK109 shows anti-tumour effects against a number of human tumour cell lines by inhibiting DNA topoisomerase II activity through the stabilization of the cleavable complex. Further, its efficacy against several drug-resistant tumour cell lines was also shown. NK109 showed potent anti-tumour activity against doxorubicin-resistant human tumour cell lines that have a typical multidrug resistance phenotype caused by P-glycoprotein. NK109 was not pumped extracellularly by P-glycoprotein and, consequently, NK109 accumulated in resistant cells. Cisplatin-resistant human tumour cell lines, which demonstrated decreased cisplatin accumulation, were sensitive to NK109. NK109 non-cross-resistance was confirmed using xenografts of tumour cells that were resistant to cisplatin in SCID mice. Furthermore, etoposide-resistant cells, with decreased topoisomerase II activity, were markedly sensitive to NK109 when compared with their parent cells, suggesting the possibility that the cytotoxic mechanism of NK109 differs from that of etoposide. In conclusion, NK109 is a very promising new anti-tumour drug for clinical use, because the efficacy of NK109 is not susceptible to several known molecular alterations that are associated with drug resistance. A clinical study of this compound is now in progress in Japan.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy.

Progressive expansion of the mesangial matrix is one of the most characteristic histological features of diabetic nephropathy (DN). To determine the balance between the turnover and degradation of extracellular matrix (ECM) in renal tissue of patients with DN, we examined the expression of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and type IV collagen (IV-C) mRNAs using a high-resolution in situ hybridization. Patients were divided into three grades: mild (grade I), moderate (grade II) and severe (grade III) mesangial expansion and tubulointerstitial injury. The relationship between the expression of these mRNAs and degree of glomerular mesangial expansion and interstitial injury was also examined. Cells positive for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman's capsule. A number of tubular epithelial cells and some infiltrating cells in the interstitium also expressed these mRNAs. The expression of MMP-3 mRNA and TIMP-1 mRNA was strongest in glomeruli of grade I and inversely correlated with mesangial expansion. In contrast, the expression of all three types of mRNA was correlated with the degree of interstitial injury. Our results indicate that IV-C, MMP-3 and TIMP-1 mRNAs are expressed in glomerular resident cells, tubular epithelial cells and infiltrating cells in renal tissue of DN, and suggest that their expression changes with the degree of mesangial expansion and interstitial injury. Altered expression of MMP-3 and TIMP-1 may be associated with the progression of DN.

Adult↗
PubMed1997

Aspergillus fumigatus Asp fI DNA is prevalent in sputum from patients with coal workers' pneumoconiosis.

Aspergillus fumigatus is an apportunistic nosocomial pathogen in immunosuppressed patients or in the lesion where the local defense mechanism was impaired. Patients with pneumoconiosis are known to be susceptible to chronic necrotizing pulmonary aspergillosis. Therefore, we hypothesized that A. fumigatus might be prevalent in sputum from patients with coal workers' pneumoconiosis, and also that asthmatic symptoms in patients with coal workers' pneumoconiosis may be associated with the presence of A. fumigatus. We tested for A. fumigatus in the sputum from patients with coal workers' pneumoconiosis by nested polymerase chain reaction amplification of the Asp fI gene. Sequences specific for this gene were detectable in 5 of 11 (45.5%) patients with coal workers' pneumoconiosis with asthmatic symptoms (group A), 5 of 10 (50.0%) patients with coal workers' pneumoconiosis without asthmatic symptoms (group B) and only 1 of 9 (11.1%) patients with chronic airflow obstruction without pneumoconiosis (group C). The frequency of the Asp fI gene detection was significantly higher in groups A and B than in group C (p < 0.05). The prevalence of A. fumigatus was not associated with asthmatic symptoms. These results demonstrated that A. fumigatus was prevalent in patients with coal workers' pneumoconiosis. We speculate that colonization with A. fumigatus may be associated with this disease.

Aged↗
PubMed1997

Apoptosis and expression of Fas/Fas ligand mRNA in bleomycin-induced pulmonary fibrosis in mice.

The incidence of apoptosis and the expression of Fas antigen (Fas)/Fas ligand (FasL) mRNA in bleomycin-induced pulmonary fibrosis in mice were examined. Male ICR mice were intratracheally instilled with bleomycin (5 U/kg of body weight). The controls were injected with sterile saline. The animals were anesthetized and killed at 1, 6, and 12 h, and 1, 3, 5, 7, 9, and 14 days after bleomycin instillation. We assessed the incidence of apoptosis in lung tissues by DNA fragmentation on agarose gel electrophoresis, terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling, and electron microscopy. The expression of Fas and FasL mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR). The localization of Fas mRNA was analyzed by in situ hybridization and that of FasL mRNA was analyzed by RT in situ PCR. The results showed that (1) a single instillation of bleomycin leads to the rapid appearance of apoptosis in bronchial and alveolar epithelial cells, which resolves within 1 day, and (2) apoptosis reappears on day 7 and continues for over 14 days after bleomycin instillation. This was accompanied with a progression of fibrosis. Corticosteroid administration completely blocked both apoptosis and fibrosis. The expression of Fas mRNA was upregulated in the alveolar epithelial cells by the bleomycin instillation. FasL mRNA was also upregulated in infiltrating lymphocytes after bleomycin treatment, but not in the control mice. The administration of corticosteroids suppressed the expression of Fas and FasL mRNA as well as apoptosis and fibrosis. Although these results do not show that apoptosis mediated by the Fas/FasL system is directly linked to bleomycin-induced fibrosis, we speculate that excessive apoptosis and the Fas/FasL system play a role in the pathogenesis of bleomycin-induced lung injury.

Animals↗
PubMed1997

Detection of adenovirus E1A DNA in pulmonary fibrosis using nested polymerase chain reaction.

The history of patients with idiopathic pulmonary fibrosis (IPF) shows that the disease may be preceded by a viral-like illness. Although viruses have not been demonstrated, it is possible that viruses were not detected in culture because they do not replicate during latency. We investigated the presence of adenovirus in IPF and interstitial pneumonia associated with collagen vascular disease (CVD-IP), using the nested polymerase chain reaction (PCR) and in situ hybridization (ISH) for the E1A region of the adenovirus genome. Studies were performed on lung tissues obtained by transbronchial lung biopsy from 19 patients with IPF, 10 patients with CVD-IP and, for comparison, from 20 patients with sarcoidosis. The E1A DNA was present in 3 out of 19 (16%) cases of IPF, in 5 of 10 (50%) cases of CVD-IP, and in 2 of 20 (10%) cases of sarcoidosis. The incidence of E1A DNA in CVD-IP was significantly higher than that in sarcoidosis (p<0.05). In patients with IPF and CVD-IP, E1A DNA was more prevalent in patients treated with corticosteroids (6 out of 9 cases; 67%) than in those without it (2 out of 20 cases; 10%) (p<0.01). ISH studies showed that 1 out of 8 cases of IPF and CVD-IP, in which E1A DNA was detected by PCR, was positive for E1A DNA. We conclude that adenovirus E1A is unlikely to be aetiologically involved in the pathogenesis of idiopathic pulmonary fibrosis or interstitial pneumonia associated with collagen vascular disease. However, a latent adenovirus infection may be reactivated or may newly infect the host following corticosteroid administration.

Adenovirus Infections, Human↗
PubMed1997

Apoptosis and Fas/Fas ligand mRNA expression in acute immune complex alveolitis in mice.

Deoxyribonucleic acid (DNA) strand breaks as a characteristic of apoptosis, and Fas antigen (Fas)/Fas ligand (FasL) expression may participate in acute immune complex alveolitis in mice. Male Institute for Cancer Research (ICR) mice were injected intravenously with immunoglobulin G (IgG) antibodies against ovalbumin and inhaled an aerosolized oval albumin (OA) solution. They were killed at 4, 6, 12, 24, 48 h and 7 days after aerosolization. We assessed DNA fragmentation by agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labelling (TUNEL). The expression of Fas and FasL messenger ribonucleic acid (mRNA) in lung tissues was assessed by reverse transcriptase (RT) polymerase chain reaction, and by in situ hybridization (ISH) to localize Fas mRNA, and RT in situ polymerase chain reaction to localize FasL mRNA. The fragmentation of DNA extracted from lung tissue was found 6-24 h after OA inhalation. TUNEL detected positive signals in bronchial and alveolar epithelial, endothelial and inflammatory cells in the lung tissue. These positive signals had disappeared 7 days after OA inhalation. TUNEL also detected positive signals in apoptotic neutrophils in bronchoalveolar lavage fluid at 6-12 h. Fas mRNA was expressed in the alveolar epithelial and inflammatory cells, while the expression of FasL mRNA appeared to be upregulated in infiltrating inflammatory cells at 6-24 h. These results suggest that apoptosis may be associated with the resolution of inflammation and with tissue repair and also suggest the involvement of the Fas antigen/Fas ligand pathway in acute immune complex alveolitis in mice.

Acute Disease↗
PubMed1997

P53 and p21 (Waf1/Cip1) mRNA expression associated with DNA damage and repair in acute immune complex alveolitis in mice.

The tumor suppresser p53 is a cell cycle checkpoint protein that contributes to the preservation of genetic stability by mediating either a G1 arrest or apoptosis in response to DNA damage. p53 causes growth arrest through transcriptional activation of the cyclin-dependent kinase inhibitor p21. During p53-mediated suppression of cell proliferation, p21 is important for coordinating cell cycle progression, DNA replication, and repair of damaged DNA. The purpose of this study is to investigate the expression of p53 and p21 mRNA in association with DNA damage and normal repair in acute immune complex alveolitis in mice. Male ICR mice were injected intravenously with IgG antibodies against oval albumin, aerosolized with oval albumin solution, and killed at 4, 6, 12, 24, and 48 hours and 1 week after aerosolization. We assessed the expression of p53 and p21 mRNA by reverse transcriptase (RT)-PCR and by RT in situ PCR. We also assessed DNA damage by terminal deoxynucleotidyl transferase mediated biotin-dUTP nick-end-labeling (TUNEL) and by gel electrophoresis of DNA extracted from lung tissues. The results of RT-PCR and RT in situ PCR showed that p53 and p21 mRNA were concurrently up-regulated at 4 to 48 hours after aerosolization in alveolar epithelial cells. Bronchial and alveolar epithelial cells were positively stained by TUNEL in this period but not at 1 week after aerosolization or in control mice. The result of electrophoretic analysis of DNA was compatible with that of TUNEL. These studies suggest that the responses of p53 and p21 mRNA are associated with physiologic processes of DNA damage and repair in acute immune complex alveolitis in mice.

Animals↗
PubMed1997

[Spontaneous recovery from cytomegalovirus pneumonia].

A 30-year-old woman with systemic lupus erythematosus was admitted to our hospital because of a slight fever and diffuse interstitial shadows on a chest X-ray film. She had taken prednisolone (60 mg per day) at another hospital for six weeks. At the time of admission to our hospital, she had been treated with antituberculosis drugs (streptomycin, isoniazid, and rifampicin) for two weeks because of suspected miliary tuberculosis. Chest radiography on admission revealed diffuse nodular and micronodular shadows in the middle and lower lung fields on both sides. Examination of transbronchial lung biopsy specimens revealed intranuclear viral inclusion bodies in infected alveolar epithelial cells, which suggested the diagnosis of cytomegalovirus infection. The elevation of serum IgM antibody to cytomegalovirus and positive results of in situ hybridization for cytomegalovirus DNA supported this diagnosis. The symptoms and radiographic abnormalities resolved completely without ganciclovir. Although we cannot exclude the possibility that the antituberculosis drugs caused the resolution of the cytomegalovirus pneumonia, it appears most probable that the cytomegalovirus pneumonia resolved spontaneously.

Adult↗
PubMed1997

Expression of thromboxane synthase in kidney tissues from patients with IgA nephropathy.

Thromboxane A2 (TXA2) is a potent vasoconstrictor which is known to be involved in the pathogenesis of experimental glomerulonephritis, although its exact pathogenic significance is not clear in human glomerulonephritis. We have investigated the expression of thromboxane synthase (TXS) in kidney tissues from patients with IgA nephropathy (IgAN), using RT-PCR and immunohistochemical methods. Biopsied renal tissues from thirty-four patients with IgAN (24 whole tissues and 10 isolated glomeruli) and normal renal tissues from 11 nephrectomized kidneys (control, eight whole tissues and three isolated glomeruli) were included in this study. TXS mRNA expression was observed in 10 out of 24 (42%) whole tissue specimens from IgAN, but no such message was disclosed in the control tissue. There was no detectable TXS mRNA expression in the isolated glomeruli either from IgAN patients or controls, although constant mRNA expressions for GAPDH and VPF/VEGF were observed. IgAN patients with positive TXS mRNA had significantly reduced GFR with elevated serum creatinine and serum beta 2-microglobulin levels. Immunostaining, using a monoclonal anti-TXS antibody, identified the localization of the TXS protein in the interstitial areas where monocyte/macrophage infiltration was abundant, as well as in the arterioles of the kidney tissues with advanced tissue damage. It was concluded that TXA2 produced by the interstitial infiltrating cells during the inflammatory process might be involved in the progression of IgA nephropathy.

Creatinine↗
PubMed1997

[Radiation therapy for uterine cervix cancer: importance of evaluation of pre-treatment tumor size with MR imaging].

From May 1992 through December 1995, a total of 42 patients with previously untreated squamous cell carcinoma of the uterine cervix were treated by using middle-dose-rate intracavitary therapy, and their previously treated local tumor volume was evaluated with MRI. According to the staging of FIGO, 2 patients were classified as Stage IB, 2 as IIA, 18 as IIB, 1 as IIIA, 14 as IIIB, 2 as IVA and 3 as IVB. Cumulative 3-year survival rates were 89% in Stage IIB and 54% in IIIB. 3-year local control rates were 100% in Stage IIB and 67% in IIIB. On the other hand, the cumulative survival rate for the local control group in all stages was 100% at 2 years and 82% at 3 years. For the pelvic failure group it was 41% at 2 years. All of those in the pelvic failure group had bulky local tumor sizes of more than 60 mm in the previous treatment MRI study. The 3-year cumulative survival rate and local control rate for tumors less than 60 mm were 84% and 100%, but for tumors over 60 mm the respective rates were 45% and 33% (p < 0.01). The a results showed that the group with pretreatment of local tumors over 60 mm on MRI had a poor outcome. We concluded that pretreatment tumor volume is an important factor in prognosis and the evaluation of pretreatment tumor volume by imaging study (MRI) is necessary.

Adult↗
PubMed1997

Convulsions in hemodialysis (HD) patients with elevated polymorphonuclear leukocyte elastase (PMNE) levels.

Eight hemodialysis (HD) patients with convulsions of unknown cause were monitored for serum levels of uremic toxins such as methylguanidine(MG), and polymorphonuclear leukocyte elastase (PMNE). Twenty HD patients without convulsions served as controls. In the convulsion group, MG and PMNE were high. In 2 patients, convulsions subsided after daily hemodiafiltration (HDF). Although PMNE was thought to be a mediator of injury in the present series, no significant correlation was found between PMNE and either neutrophil numbers or endotoxin levels. PMNE may indicate the over production of cytokines not associated with serious infection or septicemia. In patients with renal failure and complications of unknown cause, intensified dialysis therapy such as frequent HDF may be useful when combined with treatment of the underlying disease producing the toxins. PMNE measurement is useful in assessing the uremia caused by high cytokine levels and, together with methylguanidin (MG) serum levels, can indicate the severity of the convulsion.

Aged↗
PubMed1996

Studies of cardiotonic agents. 8. Synthesis and biological activities of optically active 6-(4-(benzylamino)-7-quinazolinyl)-4,5-dihydro-5-methyl-3(2H)- pyridazinone (KF15232).

We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (+/-)-1, KF15232) showed potent cardiotonic activity with a strong myofibrillar Ca(2+)-sensitizing effect. As an extension of our work, we attempted to synthesize optically active 1. (+/-)-4-(4-(Benzylamino)-7-quinazolinyl)-3-methyl-4-oxobutyric acid (-)-menthyl ester (6) was separated into both diastereoisomers, and each was converted to optically pure 1 (> 99% ee) in an enantioselective manner. In order to determine the absolute configuration of the isomers, an alternative synthesis of optically active 1 was employed. The precursor of (-)-1 ((+)-9) was obtained by enantioselective synthesis from (R)-D-alanine. Consequently, we concluded that the absolute configuration of (-)-1 at the 5-position of the pyridazinone ring was R. The cardiotonic effects and inhibitory activities to PDE III and V of racemic 1 and (-)-1 were more potent than those of (+)-1. These compounds also demonstrated greater vasorelaxant effects in guinea pig aorta. In contrast, (+)-1 showed only weak cardiotonic and vasodilating effects, although the compound displayed potent Ca(2+)-sensitizing activity. Racemic and (-)-1 attracted our interest for the treatment of congestive heart failure.

Animals↗